The Influence of Pregnancy and Lactation on Maternal Bone Health: A Systematic Review

Osteoporosis is considered as an important public health problem especially in postmenopausal women. There are some hypotheses support the contributory effect of pregnancy and lactation on osteoporosis later in life. High calcium demand during pregnancy and lactation and low estrogenic state support those hypotheses. Numerous studies have investigated on the issue but there is no consensus about the contributory effect of pregnancy and lactation on osteoporosis. To explore the current state of fact, in the present study, all bibliographic databases were searched and all relevant studies on the topic of osteoporosis, lactation, and pregnancy were reviewed. The review shows that despite of controversial results, pregnancy may have protective effect on bone especially if followed by lactation.

Osteoporosis is a chronic metabolic bone disease developing in both genders, but osteoporosis in postmenopausal women is of higher importance and is considered as a public health problem. Investigations try to better understand pathogenesis of osteoporosis, bone metabolism and the role of inflammatory pathways as well as the link with chronic senile diseases to find superior ways of prevention or treatment (1)(2)(3)(4)(5). Several contributory factors are considered essential in regulating bone metabolism as well as reaching peak bone mass in C C C Correspondence: orrespondence: orrespondence: orrespondence: Pooneh Salari,No. 21,16 Azar Ave., Keshavarz Blvd., Tehran 1417863181, Iran Email: poonehsalari@gmail.com young ages (6)(7)(8)(9)(10)(11). Both pregnancy and lactation are physiologic conditions mostly occurring in young women aged ≤ 40 years, in which calcium homeostasis is high. Pregnancy and lactation are proposed as two risk factors for postmenopausal osteoporosis but the studies do not support the hypothesis. Studies show 4-6% bone loss during the first six months of lactation because of hypoestrogenic state and calcium loss in breast milk (12). However there is no consensus about bone loss during lactation or the long-term effects of pregnancy and lactation on bone.
High calcium demand during pregnancy and lactation make women more prone to bone resorption and subsequent osteoporosis. Although hormonal changes cause calcium loss and result in increased bone resorption, bone resorption may be reversed Calcium homeostasis is significantly altered during pregnancy and lactation. In pregnancy 2-3% of maternal calcium is transferred to fetus mostly in the second and third trimester (15). During lactation 300-400 mg calcium per day is transferred into breast milk (16). Accordingly, many regulatory mechanisms such as renal calcium reservation, intestinal absorption, and bone resorption are stimulated (17). Because of high calcium demand during pregnancy, the rate of intestinal calcium reabsorption and bone turnover are increased (18). In the lactation period, calcium is preserved by kidneys to maintain bone metabolism (19). Despite of the involvement of several counter-regulatory pathways during pregnancy, bone mineral density decreases about 3%. The bone loss is counterbalanced by higher circulating levels of dihydroxyvitamin D, changes in parathyroid hormone (PTH), growth hormone, prolactin, estrogen, nutritional habits, body weight, and lifestyle (20,21). Little is known about the regulatory mechanism of calcium metabolism during lactation, but it is mostly mediated by PTH-related peptide (PTHrP) and hypoestrogenic state (16).
During pregnancy PTHrP is secreted from maternal and fetus tissues which increases dihydroxyvitamin D3, suppresses PTH, controls placental calcium transport and protects maternal skeleton (22). Furthermore, during pregnancy and subsequent lactation, the ovarian activity is low (23). During lactation, increased estrogen level may equalize the imbalance between bone resorption and bone formation (24). Estrogen deficiency during postpartum amenorrhea causes bone loss and a positive association between serum estradiol and postpartum bone mineral density (BMD) was determined (25) but the importance of estrogen is not fully understood. Meanwhile menses resumption has been proposed as a major modulator of bone metabolism after pregnancy and lactation (26).
Taken together, high calcium demand and estrogen deficiency stimulate bone metabolism during pregnancy and lactation.
Pregnancy, lactation and bone Pregnancy, lactation and bone Pregnancy, lactation and bone Pregnancy, lactation and bone Available clinical and epidemiological data do not support permanent bone loss during pregnancy and lactation (27) and there is no consensus on the longterm effect of pregnancy and lactation on bone mass. What is the blind spot is the longitudinal effects of pregnancy and lactation on BMD and prevalence of osteoporosis. Because of a potent correlation between lactation and pregnancy, both are considered as a combined risk factor.

BMD changes in pregnancy and lactation BMD changes in pregnancy and lactation BMD changes in pregnancy and lactation BMD changes in pregnancy and lactation
Pearson et al showed non-significant 1% decline in BMD at spine and hip during pregnancy and a constant pattern of bone loss during lactation especially at spine. In addition they reported restoration of 5% of the preconceptual BMD value at spine and trochanter with less recovery at total hip (28). Kolle et al observed the association of low BMD and previous pregnancy in Norwegian premenopausal women (29). In a cohort of healthy postpartum women Holmberg-Marttila et al determined systematic site specific pattern of bone loss during postpartum amenorrhea (PPA) and bone restoration after menses resumption affecting by lactation habits (30). Details of studies are summarized in Table 1.

Parity and bone Parity and bone Parity and bone Parity and bone
Several investigations showed long-term supportive effect of parity on bone (20,31). To & Wong observed less BMD decrement in multiparous women compared with primiparous (32).
Their results were confirmed in pre-and postmenopausal women (33,34). In contrast some researchers found high parity as a risk factor for osteoporosis (35) and indicated that having 6 children or more is associated with low spinal and hip BMD in postmenopausal women (36). Parra-Cabrera et al retrospectively assessed the effect of pregnancy on BMD in women aged (26-73 years) and reported detrimental effects of the number of pregnancies on BMD (37). Several other studies could not show the association between bone density and parity or lactation even in long term (38)(39)(40)(41).
Some studies reported a weak to moderate protective effect of parity on risk of fracture (42,43) while the results of the study of Parazzini et al. are against it (44). Details of the studies appeared in Table 2.

Lactation and bone Lactation and bone Lactation and bone Lactation and bone
It was reported that bone metabolism is higher in lactating mothers with longer period of breastfeeding than that of non-lactating mothers (45). It is hypothesized that after discontinuing breast feeding, bone resorption returns to normal while bone formation continues (46). During lactation, 4-7% bone loss occurs in lumbar spine and femoral neck which is reversed about one year after weaning in a site specific manner (47,48). Therefore bone loss during lactation seems to be partial (49) and there is the possibility of complete restoration of bone density (50,51).
Although some former studies insisted on the protective effect of lactation on BMD (52,53), new studies indicate detrimental effects (54,55) while some others showed no significant impact (56). In addition there are some reports of negative relationship between duration of lactation and BMD (57)(58)(59) and some reports of no relationship (60). Likewise, the results of such studies in Japan, America and Sri Lanka showed opposite results (61, 62).
More et al measured BMD in pregnant women and observed that bone mass recovery continues until 12 months postpartum in women with less than one month breastfeeding. In mothers with up to 6 months breastfeeding, bone loss stops 6 months after delivery and 6 months later, it reaches baseline level. In addition, they found that if lactation continues for 12 months, bone mass does not reach baseline level (63).
Shilbayeh indicated lactation, its frequency (4 times or more) and duration (1-6 months) as significant protective elements of bone density (64). Dursun et al introduced total duration of breast feeding as an important predictor of lumbar spine BMD and observed significant lower BMD at spine and femur in Turkish women with longer duration of lactation (54). In contrast, Aksakal et al determined no significant effect of lactation on bone in pre-and post-menopausal Turkish women (65).
In a recent cohort study, Khoo et al indicated that duration of lactation is a negative predictor of BMD at hip and spine (58) which is in agreement with the study of Rojano-Mejia et al in Mexican women (59).
In a recent study, Wiklund et al displayed the protective effect of lactation on bone size and strength in direct correlation with its duration (66) while Yazici et al found no effect of lactation and its duration on postmenopausal women (67). Details of studies are summarized in Table 3. Table  Table Table  Table 3 Table 3: Table 3:

Parity and lactation Parity and lactation Parity and lactation Parity and lactation
The protective effects of previous lactation history and parity on bone were demonstrated in some studies (55,68,69) hence there is no consensus. Some former studies stated protective effect of parity and duration of lactation on BMD (70); some mentioned a negative association (71) and the others found no association (72)(73)(74). Kojima et al investigated the effect of parity and lactation on BMD in pre-and post-menopausal women in a cross-sectional study. They stated an inverse correlation between total lactation period and BMD in premenopausal women but found no association between them in the postmenopausal women and they concluded that lactation and parity does not have major effect on BMD later in life (75).
Zhang et al confirmed the detrimental effect of parity on BMD with no influence of lactation in postmenopausal Chinese women while in premenopausal women none of them caused significant association (76). Karlsson et al studied the effect of pregnancy and lactation in 73 women aged 20-44 years and observed significant decrease in spine and body BMD after delivery. In the first 12 months after delivery, the BMD of non-lactating mothers did not significantly change however 12 months after delivery, lumbar spine BMD showed significant increment (77). Meanwhile higher BMD loss was seen in lactating mothers. They could not find correlation between parity and BMD (77).
Hill et al reported the association of >5% increase in BMD of African Caribbean women with parity and lactation in age-adjusted models but the correlation was not significant (78). Lenora et al conducted a cross sectional study in Sri Lankan women and found no detrimental effect of parity and duration of lactation on BMD in postmenopausal women (62). In another former study Chantry et al indicated the positive association between lactation, age of pregnancy and bone (79).
In addition, ultrasonometry of the heel showed no significant association between ultrasonometry variables and parity or lactation in 2080 postmenopausal women (80). Details are summarized in Table 4. Table  Table Table  Table 4 Bone loss predisposes patients to bone fractures which may cause disabilities, and work loss and imposes high cost to the society. Based on the impact of pregnancy and lactation on bone mass, different effects can be seen. Some investigations revealed reduced risk of hip fracture due to parity (31,81,82). Kauppi et al confirmed the positive effect of parity on BMD and showed inverse association between risk of hip fracture and parity (83). The association of nulliparity with hip fracture was confirmed in several studies (84,85). Michaëlsson et al. analyzed data from a population-based case-control study in Swedish women and reported 5% reduction of hip fracture per child which was influenced by use of oral contraceptives (OCP) (86). They observed that OCP increases the risk of hip fracture with no association between duration of lactation and risk of hip fracture. Also they found no correlation between body mass index (BMI), and duration of lactation with risk of fracture (86). Specker et al considered the effect of parity on bone size and strength as the factors which reduce risk of hip fracture (87).
Huo et al observed 13% reduced risk of hip fracture in association with every 6 months increase in lactation per child in Chinese women (88). In agreement with this study, Cumming et al and Kreiger et al observed the association of reduced risk of hip fracture with duration of lactation per child in a dose-dependent fashion (89,90). In a case-control study in Thailand, addition of each child was associated with 13% reduction of risk of fracture (91) while some studies in Caucasians did not support it (31,38,86).
Naves et al. conducted a longitudinal study on Spanish women over 8 years and found pregnancy as an important protective factor for the incidence of Colles fractures (92). The results of the Mallmin et al study confirms this finding as they showed more Colles fractures in women who had never been pregnant (93).

Pregnancy, la Pregnancy, la Pregnancy, la Pregnancy, lactation and bone biomarkers ctation and bone biomarkers ctation and bone biomarkers ctation and bone biomarkers
Because of the teratogenicity of X-ray on pregnant women, some investigators measure bone biomarkers as reliable indicators of bone status. Several studies demonstrated high maternal bone turnover specifically high levels of deoxypyridinoline (DpyD) and bone alkaline phosphatase (BALP) during pregnancy and 12 months postpartum in prospective studies (94,95). Osteoprotegerin (OPG) which is a member of the tumor necrosis factor superfamily acts in counteraction with receptor activator of nuclear factor κB ligand (RANKL) and inhibits osteoclast activity. Production of OPG is induced by 17β-estradiol, increases over pregnancy and decreases during lactation (96,97). It has been known that OPG is elevated in murine pregnancy which may protect maternal skeleton (98).
Little is known about the role of OPG during pregnancy in human that might have placental origin.
One study reported no significant change in OPG during pregnancy but increased level of OPG during labor (96) (Uemura et al., 2002). Naylor et al observed significant increase in OPG and β cross-linked Ctelopeptide of type I collagen (β CTX) at 36 weeks of pregnancy followed by rapid postpartum decline (99). Their study showed no correlation between change in OPG and bone turnover or BMD (99). Vidal et al found OPG level of human milk 1000-fold higher than human serum. This high amount may prevent bone loss later in life (100). Holmberg-Marttila et al. assessed the postpartum changes in bone turnover markers and found significant postpartum decrease in β CTX (bone resorption marker) and increase in bone alkaline phosphatase (BALP), amino-terminal telopeptide of procollagen (PINP), osteocalcin (OC) (bone formation markers) as early as one month. They indicated the association of higher parity and longer history of lactation with lower bone turnover markers (45).
In a longitudinal study, Chan et al compared BMD and bone biomarkers of lactating and non lactating Chinese mothers and reported significant decrement in BMD of lactating mothers in the first six months as returned to baseline at 12 months. Serum BALP was higher in lactating mothers and serum intact PTH (iPTH) increased in both groups (105).
Carneiro et al reported higher levels of biochemical bone markers including CTX, Nterminal telopeptide (NTX), BALP, and osteocalcin in lactating mothers. They indicated the distinctive pattern of increased bone turnover in states of rapid bone loss (myeloma, cancer, etc) which displays uncoupling bone markers versus lactation and osteoblast-osteoclast coupling (106). Details of studies are summarized in Table 5 Table  Table Table  Table 5

Discussion Discussion Discussion
In spite of controversial results of the mentioned studies, some investigators suggest that pregnancy causes bone loss and if pregnancy is followed by lactation, the bone density may return to normal level while the subjective reports of pregnancy-related osteoporosis and bone fractures in lactating mothers should be also taken into account (107,108). Therefore, several contributory factors which may cause the discrepancies between results should be considered. In order to have a more cautious and accurate conclusion, we should not ignore variations in the design of different studies (comparative groups, population characteristics, number of subjects, follow up period, and statistics), timing of the postpartum studies, nutritional status of mothers, racial differences in calcium homeostasis and bone metabolism, maternal age, parity, onset of menses, duration of lactation and bone sites which show inconsistencies of data (109)(110)(111). Some studies conducted on premenopausal women while some performed on postmenopausal women and even pregnant women; as a result the wide variations between study subjects have influenced the outcomes. Retrospective studies relied on the past memory of the subjects about lactation period, lifestyle or physical activity which might be with mistakes.
Actually, different bone sites, time and the method of bone densitometry may cause the discrepancy between results (12). Different studies show controversial results in different bone sites. Early studies showed advancing trabecular bone loss during pregnancy (112), however single and dual absorptimetry did not confirm former results (113,114). More controversial results show increase in cortical bone density and decrease in trabecular bone density during pregnancy and postpartum (115,116). It has been proposed that trabecular bone (lumbar spine) is more responsive to metabolic changes than the cortical bone (femoral neck, distal radius) (117). In addition, timing of bone loss in healthy women is different in bone sites. Trabecular bone mass lessens in every decade of life while cortical bone mass does not change in the third, fourth and fifth decades (118).
The method of measuring bone density or bone metabolism may be another contributory factor. Dualenergy X-ray absorptimetry (DEXA) is the most common method of measuring bone density but because of its harmful effects on fetus, alternative methods may be used during pregnancy. Accordingly fewer studies using DEXA were performed or measured bone density and its changes during pregnancy. In the recent decade, quantitative ultrasonometry (QUS) has been used for determining bone density as a safer method in pregnant women and infants. Data obtained from QUS at the heel highly correlate with its BMD and biomechanical properties; some considered this method as sensitive as axial BMD in estimating vertebral and hip fracture (119,120). This method is inexpensive, and radiation free for measuring bone density, bone quality, and risk of fracture (121). Several investigations into the issue have been conducted by measuring bone biomarkers but bone turnover markers do not show absolute changes in bone turnover however alteration in renal function during pregnancy and lactation as well as involution of the uterus affects bone turnover markers (45). Non-fasting state, and diurnal changes seem to influence CTX levels (45). Therefore, the influence of non bone tissue and its extent should not be ignored.
Some investigators indicated the possibility of the contribution of body composition of mothers on bone mass. It has been determined that in adolescents, lean body mass and later in life, fat mass are predictors of bone mass, respectively (122). The relationship between bone loading and weight gain after delivery, increased calcium absorption during pregnancy, etc and their effects on bone mass was proposed (123) but there is no enough support for this hypothesis.
There is the possibility of age-dependent contribution. Rate of bone metabolism in adolescents is higher than adults and this may lessen their sensitivity to adoption mechanisms in pregnancy and lactation (124).
The effect of nutrition and well-defined life style should be considered. It is suggested that calcium intake can overcome the negative impact of lactation on bone mass (125 but studies show that bone loss due to lactation cannot be reversed by calcium supplementation (126); and vitamin D or PTH level is not related to bone mass change over lactation period (127). Some argue that maternal bone loss during lactation is a physiologic adaptation and cannot be prevented by calcium supplementation (128). Meanwhile, there are evidences that show decreased suckling decreases serum levels of prolactin and PTH which affects bone metabolism (127).
In contrast, maternal PTH-related peptide could provide adequate calcium for infants by stimulating bone loss (101,125) which is reversed after weaning (129). Variations in the time since last delivery and the average duration of breastfeeding per child may affect the results as well.
There are reports which show recovery of BMD in the first 6-12 months after weaning (40). Hopkinson et al compared bone mineral content (BMC) in lactating and non lactating women during 2 years. They observed loss of 0.9% of BMC, 6 months after delivery which was recovered in 24 months whereas in non-lactating women, BMC increased 0.8% by 3 months postpartum and continued more rapidly in lactating mothers (12).
Furthermore the importance of the results should be verified according to the comprehensive definition of lactation. Based on WHO definitions there are two types of breast feeding called exclusive or predominant. Exclusive breast feeding refers to absolute breast feeding for at least 4 months and if possible 6 months even no water included and predominant breast feeding refers to the breast milk as the main source of infants nourishment but the infant may get nourished with water, or juices. These definitions were not considered in the mentioned studies. In studies using questionnaire, the researcher/researchers should trust on the subjects' memory even after 2-3 decades.
The exact influence of hormonal status on bone during childbearing period is not fully known and its determination may be of great help. It has been suggested that during lactation, estrogen impose minor inhibitory effect on periosteal bone formation and permits periosteal expansion which increases bone size after weaning (130).
Keeping above points in mind, it seems that pregnancy itself may lead to bone loss but if followed by lactation, it will have protective effect on bone density while the duration of lactation and parity may modulate its effect. Further investigation on this topic by considering the study limitations, contributory factors and using new safe techniques such as QUS is highly recommended.

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Authors declare that they have no conflict of interest.